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![A) Gastrocnemius muscle biopsy specimens from patients with CLI and non-ischemic control [3] were analyzed for expression levels of MiR-138 and the housekeeping small nucleolar RNAs snoRD44 and snoRD47 by qPCR. Expression levels are presented as fold CLI/normal. n = 4; *, P<0.05 vs snoRD44 or 47, whose expression levels in CLI samples were not significantly different from normal. B) Gastrocnemius muscle biopsy specimens from mice post femoral artery resection (FAR) and non-ischemic contralateral control were analyzed for expression levels of MiR-138 and the U6 small nuclear housekeeping RNA by qPCR at times indicated. Expression levels are presented as fold FAR/normal. n = 4; * P<0.05 vs U6, whose expression levels in FAR samples were not significantly different from normal.](profile/Norbert-Weiss/publication/258639462/figure/fig6/AS:214199792869389@1428080618694/A-Gastrocnemius-muscle-biopsy-specimens-from-patients-with-CLI-and-non-ischemic-control.png)
A) Gastrocnemius muscle biopsy specimens from patients with CLI and non-ischemic control [3] were analyzed for expression levels of MiR-138 and the housekeeping small nucleolar RNAs snoRD44 and snoRD47 by qPCR. Expression levels are presented as fold CLI/normal. n = 4; *, P<0.05 vs snoRD44 or 47, whose expression levels in CLI samples were not significantly different from normal. B) Gastrocnemius muscle biopsy specimens from mice post femoral artery resection (FAR) and non-ischemic contralateral control were analyzed for expression levels of MiR-138 and the U6 small nuclear housekeeping RNA by qPCR at times indicated. Expression levels are presented as fold FAR/normal. n = 4; * P<0.05 vs U6, whose expression levels in FAR samples were not significantly different from normal.
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The Ca(2+) sensor S100A1 is essential for proper endothelial cell (EC) nitric oxide (NO) synthase (eNOS) activation. S100A1 levels are greatly reduced in primary human microvascular ECs subjected to hypoxia, rendering them dysfunctional. However mechanisms that regulate S100A1 levels in ECs are unknown. Here we show that ECs transfected with a S100...
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Purpose:
HIF-PHI (hypoxia-inducible factor prolyl hydroxylase inhibitor) was developed to improve renal anemia. This study was to evaluate the efficiency and safety of HIF-PHI in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD).
Methods:
The literature was extracted from PubMed, EMBASE, the Cochrane Central Register of Contr...
SDF-1/CXCR4 activation facilitates myocardial repair. Therefore, we aimed to activate the HIF-1α target genes SDF-1 and CXCR4 by dimethyloxalylglycine (DMOG)-induced prolyl-hydroxylase (PH) inhibition to augment CXCR4+ cell recruitment and myocardial repair. SDF-1 and CXCR4 expression was analyzed under normoxia and ischemia ± DMOG utilizing SDF-1-...
Introduction:
Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the "Molidustat Once Daily Improves Renal Anemia by Inducing EPO" (MIYABI) program, which...
Background:
Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being developed to treat anemia in patients with chronic kidney disease (CKD) without dialysis dependency.
Methods:
In total, 588 patients with a clinical diagnosis of anemia due to CKD without dialysis need and with baseline hemoglobin of 7.0-10.0 g/dL (in...
Citations
... [55] Among these, microRNA-138a (miR-138a) has emerged as an intriguing candidate, particularly for bone-related applications. [56] It negatively influences angiogenic and osteogenic processes, acting as a negative regulator of the hypoxia-inducible factor [57] and -catenin. [58] Therefore, by delivering an inhibitor of miR-138 (antagomiR-138), we can potentially stimulate both angiogenesis and osteogenesis, essential processes in bone regeneration, at the same time. ...
... Among various miRNAs involved in bone healing, miR-138 has been identified as a negative regulator of osteogenesis [66] and angiogenesis by targeting -catenin [58] or hypoxia-inducible factors. [57] Thus, within Aim 1 of this study, we proposed to use a miR-138 inhibitor (antagomiR-138) to positively influence osteogenesis and bone regeneration. The antagomiR-138 was effectively delivered to the human MSCs in vitro using the non-viral nanohydroxyapatite vector in combination with the CHA scaffold. ...
Treating bone infections and ensuring bone repair is one of the greatest global challenges of modern orthopaedics, made complex by antimicrobial resistance (AMR) risks due to long‐term antibiotic treatment and debilitating large bone defects following infected tissue removal. An ideal multi‐faceted solution would eradicate bacterial infection without long‐term antibiotic use while simultaneously stimulating osteogenesis and angiogenesis. Here, we developed a multifunctional collagen‐based scaffold that addresses these needs by leveraging the potential of antibiotic‐free antimicrobial nanoparticles (copper‐doped bioactive glass, CuBG) to combat infection without contributing to AMR in conjunction with microRNA‐based gene therapy (utilising an inhibitor of microRNA‐138) to stimulate both osteogenesis and angiogenesis. CuBG scaffolds reduced the attachment of gram‐positive bacteria by over 80%, showcasing antimicrobial functionality. The antagomiR‐138 nanoparticles induced osteogenesis of human mesenchymal stem cells in vitro, and healed a large load‐bearing defect in a rat femur when delivered on the scaffold. Combining both promising technologies resulted in a multifunctional antagomiR‐138‐activated CuBG scaffold inducing hMSC‐mediated osteogenesis and stimulating vasculogenesis in an in vivo chick chorioallantoic membrane model. Overall, this multifunctional scaffold catalyses killing mechanisms in bacteria while inducing bone repair through osteogenic and angiogenic coupling, making this platform a promising multi‐functional strategy for treating and repairing complex bone infections.
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... At 3 months, miRNA-138, miR-152, miR-196a, and miR-190a were downregulated and had the best diagnostic discriminatory power to detect coronary atherosclerosis. miR-138 has been described to be atheroprotective by reducing coronary endothelial cell injury 34 and regulating endothelial dysfunction 35 . Similarly, miR-152 exhibited atheroprotection by targeting KLF5 and reducing inflammation in mice 36 and its expression levels were lower in patients with coronary artery atherosclerosis 24,29 . ...
Atherosclerosis is a complex progressive disease involving intertwined biological mechanisms. We aimed to identify miRNA expression dynamics at the early stages of atherosclerosis using a large swine model (Wisconsin Miniature Swine, WMS). A total of 18 female pigs; 9 familial hypercholesterolemic (WMS-FH) and 9 normal control swine (WMS-N) were studied. miRNA sequencing was performed on plasma cell-free RNA at 3, 6, and 9 months of age. RT-qPCR validated DE miRNAs in a new cohort of animals (n = 30) with both sexes. Gene ontology and mRNA targets for DE miRNAs were identified. In vivo multimodality imaging and histopathology were performed to document the presence of atherosclerosis at termination. 20, 19, and 9 miRNAs were significantly DE between the groups at months 3, 6, and 9, respectively. Most DE miRNAs and their target genes are involved in human atherosclerosis development. Coronary atherosclerosis was documented in 7/9 WMS-FH pigs. Control animals had no lesions. miR-138, miR-152, miR-190a, and miR-196a showed a significant diagnostic power at month 3, whereas miR-486, miR-126-3p, miR-335, and miR-423-5p were of significant diagnostic power at month 9. In conclusion, specific DE miRNAs with significant discriminatory power may be promising biomarkers for the early detection of coronary atherosclerosis.
... Increased miR-138 expression was also shown in muscle tissue from both CLI patients and mice subjected to femoral artery resection. 76 Bioinformatic analysis indicated that miR-138 could potentially bind to the 3'UTR of S100A1, which is a Ca 2 + sensor essential for nitric oxide synthase activation. Subsequent tests supported the claim that miR-138 acts through the S100A1-3'UTR. ...
... Subsequent tests supported the claim that miR-138 acts through the S100A1-3'UTR. 76 Other miRNAs identified related to antioxidant functions are miR-130a and miR-27b. Those miRNAs have both been shown to be increased in the blood of PAD patients, and bioinformatic analysis has linked both to oxidative stress pathways. ...
Peripheral artery disease (PAD) is a disease of atherosclerosis in the lower extremities. PAD carries a massive burden worldwide, while diagnosis and treatment options are often lacking. One of the key points of research in recent years is the involvement of microRNAs (miRNAs), which are short 20-25 nucleotide single-stranded RNAs that can act as negative regulators of post-transcriptional gene expression. Many of these miRNAs have been discovered to be misregulated in PAD patients, suggesting a potential utility as biomarkers for PAD diagnosis. miRNAs have also been shown to play an important role in many different pathophysiological aspects involved in the initiation and progression of the disease including angiogenesis, hypoxia, inflammation, as well as other cellular functions like cell proliferation and migration. The research on miRNAs in PAD has the potential to lead to a whole new class of diagnostic tools and treatments.
... miR-138 (miRNA-138) expression is increased in PASMCs and PAECs induced by hypoxia [33,34]. It represses hypoxia-induced apoptosis in PASMCs by down-regulating Mst1, an Akt inhibitor which represses the PI3K/Akt pathway [33]. ...
... It represses hypoxia-induced apoptosis in PASMCs by down-regulating Mst1, an Akt inhibitor which represses the PI3K/Akt pathway [33]. miR-138 is also essential in endothelial cell dysfunction, another hallmark of pulmonary arterial hypertension [34]. ...
Pulmonary hypertension (PH) is a fatal and untreatable disease, ultimately leading to right heart failure and eventually death. microRNAs are small, non-coding endogenous RNA molecules that can regulate gene expression and influence various biological processes. Changes in microRNA expression levels contribute to various cardiovascular disorders, and microRNAs have been shown to play a critical role in PH pathogenesis. In recent years, numerous studies have explored the role of microRNAs in PH, focusing on the expression profiles of microRNAs and their signaling pathways in pulmonary artery smooth muscle cells (PASMCs) or pulmonary artery endothelial cells (PAECs), PH models, and PH patients. Moreover, certain microRNAs, such as miR-150 and miR-26a, have been identified as good candidates of diagnosis biomarkers for PH. However, there are still several challenges for microRNAs as biomarkers, including difficulty in normalization, specificity in PH, and a lack of longitudinal and big sample-sized studies. Furthermore, microRNA target drugs are potential therapeutic agents for PH treatment, which have been demonstrated in PH models and in humans. Nonetheless, synthetic microRNA mimics or antagonists are susceptible to several common defects, such as low drug efficacy, inefficient drug delivery, potential toxicity and especially, off-target effects. Therefore, finding clinically safe and effective microRNA drugs remains a great challenge, and further breakthrough is urgently needed.
... In our study, higher expression of hsa-miR-138-5p was associated with a smaller size of atherosclerosis plaque (Table 2, Figure 1). Previously, hypoxia-induced elevation of miR-138 expression was observed in endothelial cells and was found to induce endothelial dysfunction, related to reduction in proliferation, angiogenesis, and VEGF-stimulated NO (nitric oxide) production by targeting the S100A1 gene [49]. This miRNA is downregulated in many types of cancers and primarily acts as a tumor suppressor by targeting many genes associated with cell proliferation, migration, and apoptosis [50,51]. ...
Lower extremity artery disease (LEAD) is an underdiagnosed and globally underestimated vascular disease caused by the progressive and chronic formation of atherosclerotic plaques in the arteries of the lower limbs. Much evidence indicates that the abnormal course of pathophysiological processes underlying LEAD development is associated with altered miRNA modulatory function. In the presented study, relationships between miRNA expression and clinical indicators of this disease (ABI, claudication distance, length of arterial occlusion, Rutherford category, and plaque localization) were identified. MiRNA expression profiles were obtained using next-generation sequencing in peripheral blood mononuclear cells (PBMCs) of 40 LEAD patients. Correlation analysis performed using the Spearman rank correlation test revealed miRNAs related to ABI, claudication distance, and length of arterial occlusion. In the DESeq2 analysis, five miRNAs were found to be dysregulated in patients with Rutherford category 3 compared to patients with Rutherford category 2. No miRNAs were found to be differentially expressed between patients with different plaque localizations. Functional analysis performed using the miRNet 2.0 website tool determined associations of selected miRNAs with processes underlying vascular pathology, such as vascular smooth muscle cell differentiation, endothelial cell apoptosis, response to hypoxia, inflammation, lipid metabolism, and circadian rhythm. The most enriched functional terms for genes targeted by associated miRNAs were linked to regulation of the cell cycle, regulation of the transcription process, and nuclear cellular compartment. In conclusion, dysregulations of miRNA expression in PBMCs of patients with LEAD are indicative of the disease and could potentially be used in the prediction of LEAD progression.
... 9,12 MiR-138 is an important miRNA associated with hypoxiainduced endothelial dysfunction. 15 In addition, SAL can induce miR-138 downregulation, thus to attenuate highglucose-induced injury of retinal pigment epithelial cells. 12 However, it is unknown whether SAL can target miR-138 to regulate hypoxia-induced retinal microvascular endothelial cell damage. ...
... 25 Moreover, Sen et al. reported miR-138 expression was enhanced in hypoxia-induced endothelial cells, and contributed to endothelial cell dysfunction. 15 These studies suggested miR-138 might contribute to hypoxia-induced injury. Similar to these reports, 12,15,25 we confirmed that miR-138 could increase hypoxia-induced HRMECs injury by abolishing the protective function of SAL, which also indicated SAL repressed hypoxia-induced HRMECs injury via decreasing miR-138. ...
... 15 These studies suggested miR-138 might contribute to hypoxia-induced injury. Similar to these reports, 12,15,25 we confirmed that miR-138 could increase hypoxia-induced HRMECs injury by abolishing the protective function of SAL, which also indicated SAL repressed hypoxia-induced HRMECs injury via decreasing miR-138. ...
Purpose:
Retinopathies are associated with the injury of retinal microvascular endothelial cells. Salidroside (SAL) is a medicinal supplement that has antioxidative and cytoprotective properties. We hypothesized that SAL might have a protective function in retinopathies. This research aims to explore the function and mechanism of SAL in hypoxia-induced retinal microvascular endothelial cell injury.
Methods:
Human retinal microvascular endothelial cells (HRMECs) injury was induced by culturing under hypoxic condition. The function of SAL on HRMECs injury was investigated using cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry, Western blotting, and enzyme linked immunosorbent assay. MicroRNA (miR)-138, roundabout 4 (ROBO4), and proteins in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways were examined using quantitative reverse transcription polymerase chain reaction or Western blotting. The target correlation was determined by dual-luciferase reporter analysis and RNA immunoprecipitation.
Results:
Hypoxia resulted in proliferation inhibition, cycle arrest, apoptosis, inflammatory reaction, and oxidative stress in HRMECs. SAL attenuated hypoxia-induced HRMECs injury via increasing cell proliferation, and mitigating cycle arrest, apoptosis, inflammatory reaction, and oxidative stress. MiR-138 expression was enhanced by hypoxia, and decreased via SAL stimulation. MiR-138 upregulation reversed the influence of SAL on hypoxia-induced HRMECs injury. ROBO4 was targeted via miR-138. ROBO4 overexpression weakened the role of miR-138 in HRMECs injury. The PI3K/AKT/mTOR pathway was inactivated under hypoxic condition, and SAL increased the activation of PI3K/AKT/mTOR pathways by decreasing miR-138.
Conclusions:
SAL protected against hypoxia-induced HRMECs injury through regulating miR-138/ROBO4 axis, indicating the protective potential of SAL in retinopathies.
... A considerable number of molecular functions are associated with HIF-1, which can be classified in Gene Ontology (GO) terms ( b T2 Table 2). Inferred from direct assay (biochemical or cell biological assay), and beyond oxygen homeostasis (158) and the response to hypoxia (29,102,139,211,421,430), HIF-1 is associated with neuronal survival under conditions of oxidative stress (288), vascular endothelial growth factor production (102, 177), and transcriptional regulation (29,193,207,210,212,252,349,351,408,421). However, other regulatory mechanisms appear to be involved in the hypoxic response, such as non-coding RNA and alternative splicing (314). ...
Significance:
In recent years, a number of studies have shown altered oxygen partial pressure at a tissue level in metabolic disorders, and some researchers have considered oxygen to be a (macro) nutrient. Oxygen availability may be compromised in obesity and several other metabolism-related pathological conditions, including sleep apnea-hypopnea syndrome, the metabolic syndrome (which is a set of conditions), type 2 diabetes, cardiovascular disease and cancer. Recent Advances: Strategies designed to reduce adiposity and its accompanying disorders have been mainly centered on nutritional interventions and physical activity programs. However, novel therapies are needed since these approaches have not been sufficient to counteract the worldwide increasing rates of metabolic disorders. In this regard, intermittent hypoxia training and hyperoxia could be potential treatments through oxygen-related adaptations. Moreover, living at high altitude may have a protective effect against the development of abnormal metabolic conditions. In addition, oxygen delivery systems may be of therapeutic value for supplying the tissue-specific oxygen requirements.
Critical issues:
Precise in vivo methods to measure oxygenation are vital to disentangle some of the controversies related to this research area. Furthermore, it is evident that there is a growing need for novel in vitro models to study the potential pathways involved in metabolic dysfunction in order to find appropriate therapeutic targets.
Future directions:
Based on the existing evidence, it is suggested that oxygen availability has a key role in obesity and related comorbidities. Oxygen should be considered in relation to potential therapeutic strategies in the treatment and prevention of metabolic disorders.
... Recently, Babicheva A and colleagues recently demonstrated that miR-138-5p regulated the global K + current in control human PASMCs and that a miR-138-5p antagomir partly restored the K + function in iPAH PASMCs [34]. Moreover, miR-138-5p is described to cause endothelial dysfunction and impair tube formation [35]. ...
Background:
The pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways. MicroRNAs are potential candidates involved in simultaneously coordinating multiple genes under such multifactorial conditions.
Methods and results:
MiR-138-5p is overexpressed in pulmonary arterial smooth muscle cells (PASMCs) from PAH patients and in lungs from rats with monocrotaline-induced pulmonary hypertension (MCT-PH). MiR-138-5p is predicted to regulate the expression of the potassium channel KCNK3, whose loss is associated with the development and progression of PAH. We hypothesized that, in vivo, miR-138-5p inhibition would restore KCNK3 lung expression and subsequently alleviate PAH. Nebulization-based delivery of anti-miR-138-5p to rats with established MCT-PH significantly reduced the right ventricular systolic pressure and significantly improved the pulmonary arterial acceleration time (PAAT). These haemodynamic improvements were related to decrease pulmonary vascular remodelling, lung inflammation and pulmonary vascular cell proliferation in situ. In vivo inhibition of miR-138-5p restored KCNK3 mRNA expression and SLC45A3 protein expression in the lungs.
Conclusions:
We confirmed that in vivo inhibition of miR-138-5p reduces the development of PH in experimental MCT-PH. The possible curative mechanisms involve at least the normalization of lung KCNK3 as well as SLC45A3 expression.
... Aside, miR-138 targets S100 calcium-binding protein A1 (S100A1), a protein that plays a critical role in eNOS activity. Hypoxia-induced miR-138 expression decreases the levels of S100A1, resulting in the loss of eNOS activity [79]. EC dysfunction might be partially restored by lovastatin treatment through blunting miR-133 overexpression. ...
Nowadays, the obesity pandemic is one of the most relevant health issues worldwide. This condition is tightly related to comorbidities such as non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs), namely atherosclerosis. Dysregulated lipid metabolism and inflammation link these three diseases, leading to a subsequent increase of oxidative stress (OS) causing severe cellular damage. On the other hand, microRNAs (miRNAs) are short, single-stranded, non-coding RNAs that act as post-transcriptional negative regulators of gene expression, thus being involved in the molecular mechanisms that promote the development of many pathologies including obesity and its comorbidities. The involvement of miRNAs in promoting or opposing OS in disease progression is becoming more evident. Some miRNAs, such as miR-200a and miR.421, seem to play important roles in OS control in NAFLD. On the other hand, miR-92a and miR-133, among others, are important in the development of atherosclerosis. Moreover, since both diseases are linked to obesity, they share common altered miRNAs, being miR-34a and miR-21 related to OS. This review summarizes the latest advances in the knowledge about the mechanisms of oxidative stress (OS) generation in obesity-associated NAFLD and atherosclerosis, as well as the role played by miRNAs in the regulation of such mechanisms.
... Similarly, miRNA-106b-93-25 has been shown to be involved with neovascularization processes that follow ischemia in progenitor/stems cells [31]. miRNA(s) also appear to play a role in other pathophysiological events pertinent to CLTI, such as inflammation, diabetes mellitus, and hypoxia [32][33][34][35][36][37][38]. However, the majority of these findings were discovered in animal models and are yet to be translated in CLTI patients. ...
Chronic limb-threatening ischemia (CLTI) results in devastating complications such as lower-limb amputations. In this study, a genome-wide plasma microRNAs (miRNA) sequencing was performed to identify miRNA(s) associated with CLTI. Blood samples were collected from early stage CLTI patients (ABI < 0.9) and non-PAD controls (ABI ≥ 0.9) for 3 experiments: discovery phase (n = 23), confirmatory phase (n = 52) and validation phase (n = 20). In the discovery phase, next generation sequencing (NGS) was used to identify miRNA circulating in the plasma CLTI (n = 13) patients, compared to non-PAD controls (n = 10). Two down-regulated miRNAs (miRNA-6843-3p and miRNA-6766-5p) and three upregulated miRNAs (miRNA-1827, miRNA-320 and miRNA-98-3p) were identified (≥2-fold change). In the confirmatory phase, these 5 deregulated miRNAs were further investigated in non-PAD (n = 21) and CTLI (n = 31) patients using qRT-PCR. Only miRNA-1827 was found to be significantly upregulated (≥3-fold, p-value < 0. 001) in the CLTI group. Lastly, to minimize the influence of confounding factors, miRNA-1827 plasma levels were validated in a third cohort of CLTI patients (n = 10) matched to non-PAD controls (n = 10). Our analysis demonstrated that miRNA-1827 expression was increased in the CLTI cohort (≥2-folds, p-value < 0.001). In summary, circulating miRNA-1827 is significantly elevated in patients with CLTI.
